BRPI0619570A2 - hydrophilic coating - Google Patents

Abstract

The invention relates to a hydrophilic coating formulation which when cured results in a hydrophilic coating, wherein the hydrophilic coating formulation comprises a polyelectrolyte and a non-ionic hydrophilic polymer. The invention further relates to a coating system, a hydrophilic coating, a lubricious coating, use of a polyelectrolyte and a non-ionic hydrophilic polymer in a lubricious coating, an article, a medical device or component and a method of forming on a substrate a hydrophilic coating.

Description

HYDROPHILIC COATING

This invention relates to a hydrophilic coating formulation which, when cured, results in a hydrophilic coating. The invention further relates to a coating system, a hydrophilic coating, a lubricating coating, the use of a polyelectrolyte and a non-ionic hydrophilic polymer in a lubricating coating, an article, a medical device or component, and a method of formation of a hydrophilic coating on a substrate.

Many medical devices, such as urinary and cardiovascular catheters, syringes, and membranes need to have a lubricant applied to the outer and / or inner surfaces to facilitate body insertion and removal, and / or to drain body fluids. Lubricating properties are also required in order to minimize the. soft tissue injury upon insertion or removal. Especially for lubrication purposes, such medical devices may have a hydrophilic surface coating or layer that becomes lubricated and achieves low frictional properties when moistened, i.e. applying a wetting fluid for a specified period of time prior to insertion of the device. in a patient's body. A hydrophilic surface or layer coating that becomes lubricant upon wetting will hereinafter be referred to as a hydrophilic coating. A coating obtained after wetting will hereinafter be referred to as a lubricating coating.

A well recognized problem encountered when using lubricant coatings has been the fact that coatings may lose water and dry before insertion into the body or when inside the body, it comes into contact, for example, with a mucous membrane such as when a urinary catheter is inserted into the urethra.

Of course, this affects the lubrication properties and low friction of the lubricant coating, and can lead to patient pain and injury when the device is inserted or removed from the body.

Therefore, it would be advantageous to have medical devices comprising a hydrophilic coating that remains lubricated upon application of a wetting fluid for an extended period of time before and after insertion into a patient's body. The time that the hydrophilic coating remains lubricated upon application of the wetting fluid will hereinafter be referred to as drying time.

It is an object of the present invention to provide a hydrophilic coating that remains lubricated for a long period of time when applying a wetting fluid before or after insertion into a patient's body. Surprisingly, it has now been found that a lubricating coating having a prolonged and thus improved drying time can be obtained when a polyelectrolyte and a hydrophilic, nonionic polymer are included in the hydrophilic coating, from which said lubricating coating is formed. application of a humectant fluid.

It has further been found that the water absorption ratio is increased in a coating of the invention comprising a polyelectrolyte in combination with a non-ionic hydrophilic polymer as compared to a similar coating without such components. This is specifically advantageous if the article is to be stored with a dry coating and the coating must be moistened before use. Satisfactory wetting of a coating, for example of a catheter, can thus be achieved within a few seconds after immersion in water or exposure to air at 100% relative humidity.

Within the context of the invention, "lubricant" is defined as having a sliding surface. A coating on the outer or inner surface of a medical device, such as a catheter, is considered lubricant if (when moistened) it can be inserted into the intended body part without causing injury and / or causing unacceptable levels of discomfort to the individual. . Specifically, a coating is considered lubricant if it has a friction as measured on a 20 g or less Harland FTS5000 Friction Testing Device (HFT), preferably 15 g or less, at a stapling force of 300 g, a speed 1 cm / s, a temperature of 22 ° C and a relative humidity of 35%. The protocol is as indicated in the Examples.

The term "wetted" is generally known in the art and - in a broad sense - means "containing water". Specifically, the term is used herein to describe a coating containing sufficient water to be lubricant. In terms of water contraction, generally a wetted coating contains at least 10% by weight of water based on the dry weight of the coating, preferably at least 50% by weight based on the dry weight of the coating, more preferably at least 100% by weight based on the dry weight of the coating. For example, in a specific embodiment of the invention, a water absorption of about 300-500% by weight of water is practicable.

Examples of wetting fluids are treated or untreated water, mixtures containing water, for example with organic solvents or aqueous solutions comprising, for example, salts, proteins or polysaccharides. Specifically, a wetting fluid may be a body fluid.

An important property of such a lubricant coating is that it remains lubricated for as long as necessary. Therefore, the drying time would be long enough to allow application to medical devices. Within the context of the experiment, the drying time is the length of time the coating remains lubricated after a device comprising the lubricating coating has been removed from the wetting fluid where it has been stored and / or moistened. Drying time can be determined by measuring friction in grams as a function of the time the catheter was exposed to air in HFT (see above). Drying time is the point in time where the friction reaches a value of 20 g or more or in a narrower test 15 g or more as measured at a temperature of 22 ° C and a relative humidity of 35%.

Within the context of the invention, the term polymer is used for a molecule comprising two or more repeating units. Specifically, it may be composed of two or more monomers that may be the same or different. As used herein, the term includes oligomers and prepolymers. Generally the polymers have a number average weight (Mn) of about 500 g / mol or more, specifically about 1,000 g / mol or more, although Mn may be lower if the polymer is composed of relatively small monomer units. Hereinafter, Mn is defined as Mn as determined by light scattering.

Within the context of the invention a polyelectrolyte is understood to be a high molecular weight, linear, branched or crosslinked polymer composed of macromolecules comprising constitutional units, wherein between 5 and 100% of the constitutional units contain ionized groups when the polyelectrolyte is in the lubricant coating. . Here a constitutional unit is understood to be, for example, a repetition unit, for example, a monomer. A polyelectrolyte herein may refer to a type of polyelectrolyte composed of one type of macromolecules, but it may also refer to two or more different types of polyelectrolytes composed of different types of macromolecules.

Considerations when selecting an appropriate polyelectrolyte are its solubility and viscosity in aqueous media, its molecular weight, its charge density, its affinity for a coating support network and its biocompatibility. Here, biocompatibility means biological compatibility by not producing toxic, detrimental or immunological response in living mammalian tissue.

For decreased migration capacity, the polyelectrolyte is preferably a polymer having a weight average molecular weight of at least about 1,000 g / mol, as determinable by light scattering, optionally in combination with size exclusion chromatography. A relatively high molecular weight polyelectrolyte is preferred to increase drying time and / or reduce migration out of the coating.

The weight average molecular weight of the polyelectrolyte is preferably at least 20,000 g / mol, more preferably at least 100,000 g / mol, even more preferably at least about 150,000 g / mol, specifically about 200,000 g / mol or more. To facilitate application of the coating it is preferred that the average weight is 1000,000 g / mol or less, specifically 500,000 g / mol or less, more specifically 300,000 g / mol or less.

Examples of ionized groups that may be present in the polyelectrolyte are ammonium groups, phosphonium groups, sulfonium groups, carboxylate groups, sulfate groups, sulfinic groups, sulfonic groups, phosphate groups and phosphoric groups. Such groups are very effective in water binding. In one embodiment of the invention, the polyelectrolyte also comprises metal ions. Metal ions, when dissolved in water, are complexed with water molecules to form water ions [M (H2O) x] n +, where χ is the coordination number and η the charge of the metal ion and are therefore specifically effective in the binding of Water. Metal ions that may be present in the polyelectrolyte are, for example, alkaline metal ions such as Na +, Li +, or K +, or alkaline earth metal ions such as Ca2 + and Mg2 +. Specifically when the polyelectrolyte comprises quaternary amine salts, for example quaternary ammonium groups, anions may be present. Such anions may be, for example, halides such as Cl ", Br", I "and F", as well as sulfates, nitrates, carbonates and phosphates.

Suitable polyelectrolytes are, for example, acrylic acid homo and copolymers salts, methacrylic acid homo and copolymers, maleic acid homo and copolymers salts, homo salts and fumaric acid copolymers homomer salts and monomer copolymers comprising sulfonic acid groups, homo salts and monomer copolymers comprising quaternary ammonium salts and mixtures and / or derivatives thereof. Examples of suitable polyelectrolytes are poly (acrylamide-co-acrylic acid) salts, for example poly (acrylamide-co-acrylic acid) sodium salt, poly (acrylamide-co-methacrylic acid) salts, e.g. poly (acrylamide-co-methacrylic acid) sodium, poly (methacrylamide-co-acrylic acid) salts, for example poly (methacrylamide-co-acrylic acid) sodium salts, poly (methacrylamide-co-methacrylic acid) salts, for example poly (methacrylamide-co-methacrylic acid) sodium salt, poly (acrylic acid) salts, for example poly (acrylic acid) sodium salt, poly (methacrylic acid) salts, for example poly (acid acrylic acid) salt methacrylic acid), poly (acrylic acid-co-maleic acid) salts, for example poly (acrylic-co-maleic acid) sodium salt, poly (methacrylic acid-co-maleic acid) salts, for example poly-sodium salt (acrylamide-co-maleic acid), poly (methacrylamide-co-maleic acid) salts, e.g. sodium salt poly (methacrylamide-acid) co-maleic acid), poly (acrylamido-2-methyl-1-propanesulfonic acid) salts, poly (4-styrene sulfonic acid) salts, poly (acrylamide-co-dialkyl ammonium chloride), poly [bis- (2- chloroethyl) ether-alt-1,3-bis [3- (dimethylamino) propyl] urea] quaternized, polyallylammonium phosphate, poly (diallyl dimethylammonium chloride), poly (trimethylenoxyethylene sodium sulfonate), poly (dimethyl dimodecyl (2-acrylamidoethyl) ammonium bromide), poly (2-N-methylpyridinomethylene iodine), polyvinylsulfonic acids and poly (vinyl) pyridines, polyethyleneimines and polylysine salts.

Specifically suitable polyelectrolytes for use in the present invention are copolymeric polyelectrolytes, wherein said copolymeric polyelectrolyte is a copolymer comprising at least two different types of constitutional units, where at least one type of constitutional units comprises ionizable or ionized groups and at least one type of constitutional units. not found in ionizable or ionized groups.

Ionizable is understood to be ionizable in neutral aqueous solutions, that is, solutions having a pH between 6 and 8.

Said copolymeric polyelectrolyte may be a random or block copolymer. Generally, between 5 and 99% by weight, preferably between 50 and 90% by weight, more preferably between 70 and 85% by weight of the constitutional units comprise ionizable or ionized groups. In the lubricant coating, that is, after wetting of the hydrophilic coating, the ionizable groups may be ionized or nonionized. Typically between 1 and 100 wt.% Of the total amount of the ionizable and ionized groups are ionized when the copolymer polyelectrolyte is in the lubricating coating, preferably between 30 and 100 wt.%, More preferably between 50 and 100 wt. and 100% by weight.

Examples of constitutional units comprising ionizable groups are constitutional units comprising carboxylic acid groups, for example acrylic acid, methacrylic acid, maleic acid and formic acid; sulfonic acid groups; sulfinic acid groups and phosphonic acid groups. Examples of constitutional units comprising ionized groups are constitutional units comprising salts of the ionizable groups mentioned above, that is, carboxylate groups, sulfonium groups, sulfinic groups, sulfate groups, phosphate groups, phosphonic groups, phosphonium groups and quaternary ammonium salts.

Examples of constitutional units that do not comprise ionizable groups are acrylamide, methacrylamide, vinyl alcohol, methylacrylate, methylmacrylate, vinylpyrrolidone and vinylcaprolactam.

Examples of copolymeric polyelectrolytes are poly (acrylamide-co-acrylic acid) salts, poly (acrylamide-co-methacrylic acid) salts, poly (methacrylamide-co-acrylic acid) salts, poly (methacrylamide-co-methacrylic acid) salts poly (acrylamide-co-maleic acid) salts, poly (methacrylamide-co-maleic acid) and poly (acrylamide-co-dialkyl ammonium chloride) salts. Poly (acrylamide-co-acrylic acid) salts, for example sodium salt, have been found to be specifically suitable for obtaining superior lubrication and drying time.

The use of copolymeric polyelectrolytes comprising both constitutional units consisting of ionizable or ionized groups and constitutional units that are not present in ionizable or ionized groups has numerous advantages. Generally, such polyelectrolytes have higher solubility, specific solvents and less tendency to crystallize when used in the cured hydrophilic coating.

The nonionic hydrophilic polymer is understood to be a high molecular weight branched or crosslinked polymer comprised of macromolecules comprising constitutional units, where less than 5, preferably less than 2% of constitutional units contain ionized groups when the hydrophilic polymer, nonionic is in the lubricant coating. The hydrophilic, nonionic polymer is capable of providing hydrophilicity to a coating and may be synthetic or bioderivated and may be combinations or copolymers thereof. Non-ionic hydrophilic polymers include, but are not limited to poly (lactams), for example polyvinylpyrrolidone (PVP), polyurethanes, homo and copolymers of acrylic and methacrylic acid, polyvinyl ethers, polyvinyl ethers, maleic anhydride-based copolymers, polyesters, vinylamines, polyethyleneimine, polyethylene oxides, poly (carboxylic acids), polyamides, polyanhydrides, polyphosphenes, cellulosics, for example methyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose and hydroxypropylcellulose, heparin, dextran, polypeptides, e.g. , polysaccharides, e.g. chitosan, hyaluronic acid, alginates, gelatin and chitin, polyesters, e.g. polylactides, polyglycolides and polycaprolactones, polypeptides, e.g. collagen, albumin, oligo peptides, polypeptides, short chain peptides, proteins and oligonucleotides .

It has been found that the adhesion between the initial layer and the article surface and / or the initial layer and the outer layer is improved by increasing the molecular weight of the hydrophilic, nonionic functional polymer.

Accordingly, the weight average molecular weight of the hydrophilic, nonionic functional polymer as determined by light scattering, optionally in combination with size exclusion chromatography, is generally at least 20,000 g / mol, specifically at least 55,000 g. / mol, preferably at least 250,000 g / mo; specifically at least 360,000 g / mol, more preferably at least 500,000 g / mol, specifically at least 750,000 g / mol.

For practical reasons (ease of application and / or ease of uniform coating thickness), the weight average molecular weight (Mw) is generally up to 10 million, preferably up to 5 million g / mol, more preferably up to 3 million g / mol, more preferably up to 2 million g / mol, specifically up to 1.5 million g / mol, more specifically up to 1 million three hundred thousand g / mol, even more specifically up to 1 million g / mol.

Specifically, it has been found that polyvinylpyrrolidone (PVP) and polyethylene oxide (PEO) having an Mw of at least 100,000 c / mol have a specific positive effect on lubrication and a low tendency to migrate out of the coating.

Specifically for polyvinylpyrrolidone (PVP) and polymers of the same class, a polymer having a molecular weight corresponding to at least K15, more specifically K30, even more specifically K80 is preferred. Specifically good results were obtained with a polymer having a molecular weight corresponding to at least K90. With respect to the upper limit, a K120 or less, specifically a K100 is preferred. The K value is the value as determined by Method W13 07, Revision 5/2001 of the Viscotek Y501 automated relative viscometer. This manual can be found at www, ispcorp.com/products/hairscin/index 3.html

The invention relates to a hydrophilic, nonionic coating formulation which when applied to a substrate and cured results in hydrophilic coating. Here the hydrophilic coating formulation refers to a liquid hydrophilic coating formulation, for example, a solution or dispersion comprising a liquid medium. Here any liquid medium that allows the application of a hydrophilic coating formulation on the surface would be sufficient. Examples of liquid media are alcohols such as methanol, ethanol, propanal, butanol or their isomers and aqueous mixtures thereof or acetone, methyl ethyl ketone, tetrahydrofuran, dichloromethane, toluene and aqueous mixtures or emulsions thereof. The hydrophilic coating formulation further comprises components which, when cured, are converted to the hydrophilic coating, and thus remain in the hydrophilic coating after curing. Curing herein is understood to refer to physical or chemical stiffening or solidification by any method, for example, heating, cooling, drying, crystallization or curing as a result of a chemical reaction, such as radiation curing or heat curing. Cured state, all or part of the components in the hydrophilic coating formulation may be cross-linked to form covalent bonds between all or part of the components, for example by the use of UV or electron beam radiation. However, in the cured state, all or some components may also be ionically bonded, linked by dipole-dipole interactions, or linked via Van der Waals forces or hydrogen bonds.

The term Curing includes any method of treating the formulation such that it forms a firm or solid coating. Specifically, the term includes a treatment, whereby the hydrophilic polymer further polymerizes this by being grafted such that it forms an excerpt and / or crosslinked polymer such that it forms a crosslinked polymer.

The hydrophilic coating composition according to the invention typically comprises 1-90 wt%, preferably 3-50 wt%, more preferably 5-30 wt%, specifically 10-20 wt% of the polyelectrolyte based on total weight. of the dry coating.

The hydrophilic, nonionic polymer may be used in more than 1 wt.% Of the hydrophilic coating formulation, for example more than 10 wt.%, More than 20 wt.%, Or more than 30 wt.%. based on the total weight of the dry coating. Hydrophilic, nonionic polymer may be present in the hydrophilic coating formulation up to 95 wt.%, However, more often the hydrophilic, nonionic polymer will be used up to 50, 60, 70 or 80 wt.%. total dry coating.

Hereafter, all percentages of the components provided in the application are based on the total weight of the dry coating, i.e. the hydrophilic coating formed upon curing of the hydrophilic coating composition. The invention also relates to a hydrophilic coating obtained by applying the hydrophilic coating formulation according to the invention to a substrate and curing thereof.

The invention also relates to a lubricant coating that can be obtained by applying wetting fluid to said hydrophilic coating, and to the use of a polyelectrolyte and a nonionic hydrophilic polymer in a lubricating coating in order to improve its drying time. Additionally, the invention relates to an article, specifically a medical device or medical device component comprising at least one hydrophilic coating according to the invention and to a method of forming onto a hydrophilic coating substrate according to the invention.

In one embodiment of the invention the hydrophilic coating comprises the polyelectrolyte and the nonionic hydrophilic polymer. Said hydrophilic coating is formed by curing the hydrophilic coating formulation comprising the polyelectrolyte and the nonionic hydrophilic polymer. Preferably, the polyelectrolyte and nonionic hydrophilic polymer are covalent and / or physically bonded together and / or entrapped to form a polymeric network upon curing.

In another embodiment of the invention the hydrophilic coating comprises the polyelectrolyte, the non-ionic hydrophilic polymer and a support network, which may be the hydrophilic support network, and which is formed of a support monomer or polymer. Here the supporting monomer or polymer, other than comprising various reactive fractions capable of cross-linking reactions, as described below, may also contain hydrophilic functional groups. Said hydrophilic coating is formed by curing the hydrophilic coating formulation comprising the polyelectrolyte, the hydrophilic, nonionic polymer β or the supporting monomer or polymer. Preferably the polyelectrolyte and / or hydrophilic, nonionic polymer and / or hydrophilic support network are covalently and / or physically linked together and / or entrapped to form a polymeric network upon curing.

In such embodiments, where the polyelectrolyte and / or hydrophilic, nonionic polymer and / or the supporting monomer or polymer are covalently and / or physically bonded to the hydrophilic coating as part of a polymeric network, this is specifically preferred since It has the advantage that the non-ionic polyelectrolyte and hydrophilic polymer will not leak into the environment from the hydrophilic coating, for example when it is coated on a medical device. This is specifically useful when the medical device is inside the human body or the body of an animal.

In the formulation of the hydrophilic coating that is used to produce said hydrophilic coating, the weight ratio of hydrophilic, nonionic polymer to monomer or carrier polymer may vary, for example, between 10: 90 and 90: 10, such as between : 75 and 75: 25 or such as between 60: 40 and 40: 60.

A support network may be formed upon curing a support monomer or polymer or any combination of the support monomers and polymers comprising various reactive fractions capable of undergoing cross-linking reactions, which may be present in the hydrophilic coating formulation. The reactive moiety of the supporting monomer or polymer may be selected from the group consisting of radically reactive groups such as alkenes, amino, starch, sulfhydryl (SH), unsaturated esters, ethers and amides and alkyd / dried resins. The supporting monomer or polymer may have a structure and at least one of the reactive fractions mentioned above. The support polymer structure can be selected from the group consisting of polyethers, polyurethanes, polyethylenes, polypropylenes, polyvinyl chlorides, polyepoxides, polyamides, polyacrylamides, poly (meth) acrylics, polyoxyazolidones, polyvinyl alcohols, polyethylene imines, polyesters and copolymers alkyl, polypeptides or polysarides, such as cellulose and starch or any combination of the above. Specifically, the support monomer, unsaturated ester polymers, amide or ether groups, thiol or mercaptan may be suitably used in the invention.

As used herein, the term support monomer refers to molecules with a molecular weight of less than approximately 1,000 g / mol, and the term support polymer is used for molecules with a molecular weight of approximately 1,000 g / mol or more.

Generally, the supporting monomer or polymer has a molecular weight in the range of from about 500 to about 10 to 100,000 g / mol, and preferably is a polymer with a molecular weight in the range of about 1,000 to about 10,000 g / mol. Specifically, good results were obtained with a carrier polymer in the range of about 1,000 to about 6,000 g / mol. The number of reactive groups per molecule of the support monomer or polymer is preferably in the range from about 1.2 to about 64, more preferably in the range from about 1.2 to about 16, more preferably in the range from about 1.2 to about 16. from 1.2 to about 8.

The support monomer or polymer may be used by more than 0 wt% based on the total weight of the dry coating, for example by more than 10 wt%, by more than 20 wt%, by more than 30 wt% or by weight. more than 40% by weight. The supporting monomer or polymer may be present in the hydrophilic coating formulation up to 90% by weight, however, more often the supporting monomer or polymer will be used up to 50 or 60% by weight based on the total weight of the dry coating. .

The hydrophilic coating formulation according to the invention may be used, for example, by employing visible or UV light, electron beam, plasma, gamma or IR radiation, optionally in the presence of a photoinitiator or thermal initiator to form the hydrophilic coating. Examples of photoinitiators that may be used in the hydrophilic coating are radical free photoinitiators, which are generally divided into two classes according to the process by which the initiating radicals are formed. Compounds that undergo unimolecular binding cleavage upon irradiation are termed Norrish type I or homolytic photoinitiators. A type I Norrish primer interacts with a second molecule, that is, a synergist, which can be a low molecular weight compound of a polymer in the excited state to generate radicals in a biomolecular reaction. In general, the two major reaction pathways for Norrish type II photoinitiators are hydrogen abstraction by the excited initiator or photoinduced electron transfer. Examples of suitable free radical photoinitiators are disclosed in WO 00/18696 and are incorporated herein by reference. . Water soluble photoinitiators or those which may be adjusted to become water soluble are preferred, also photoinitiators which are polymeric or polymerizable photoinitiators are preferred.

In one embodiment of the invention the polyelectrolyte is present in a wetting fluid and introduced into the hydrophilic coating when wetting the hydrophilic coating. This is specifically useful for medical devices with a hydrophilic coating that are packaged in a fluid, or where the hydrophilic coating is moistened in a separate wetting fluid containing the polyelectrolyte. The invention therefore also relates to the coating system for preparing a lubricant coating, said coating system comprising a coating formulation comprising a hydrophilic, nonionic polymer and a wetting fluid comprising a polyelectrolyte. Further the invention relates to a coating system for preparing a lubricant coating, said coating system comprising a coating formulation according to the invention and a wetting fluid comprising a polyelectrolyte.

In one embodiment of the invention the hydrophilic coating formulation according to the invention further comprises at least one surfactant which can enhance the surface properties of the coating. Surfactants constitute the most important group of detergent components. These are generally surface-active, water-soluble agents comprised of a hydrophobic moiety, generally a long alkyl chain, attached to hydrophilic or functional water solubility enhancing groups. Surfactants can be categorized according to the charge present in the hydrophilic portion of the molecule (after dissociation in the aqueous solution): ionic surfactants, for example anionic or ionic surfactants, and nonionic surfactants. Examples of ionic surfactants include sodium dodecyl sulfate (SDS), sodium cholate, sodium bis (2-ethylhexyl) sulfosuccinate salt, cetyltrimethylammonium bromide (CTAB), sodium lauryl dimethylamine oxide, sodium N-lauroylsarcosine salt and sodium deoxycholate (DOC). Examples of nonionic surfactants include alkyl polygicosides such as TRIΤΟΝ ™ BG-10 surfactant and TRITON CG-110 surfactant, secondary branched alcohol ethoxylates such as TERGITOL ™ TMN series, ethylene oxide / propylene oxide copolymers, such as TERGITOL L series and TERGITOL XD, XH and XJ surfactants, nonylphenol ethoxylates such as TERGITOL NP series, octylphenol ethoxylates such as TRITON X series, secondary alcohol ethoxylates such as TERGITOL 15- S and special alkoxylates such as TRITON CA surfactant, TRITON N-57 surfactant, TRITON X-207 surfactant, Tween 80 and Tween 20.

Typically 0.001 to 1 wt% of the surfactant is applied, preferably 0.05-0.5 wt%, based on the total weight of the dry coating.

In one embodiment of the invention the hydrophilic coating formulation according to the invention further comprises at least one plasticizer. which may improve the flexibility of the coating, which may be preferable, when the object to be coated will likely bend during use. The plasticizer may be included in the hydrophilic coating formulation at a concentration of from about 1 wt% to about 5.0 wt%. Suitable plasticizers are high boiling compounds, preferably with a boiling point at atmospheric pressure above 200 ° C, and with a tendency to remain homogeneously dissolved and / or dispersed in the coating upon curing. Examples of suitable plasticizers are mono and polyalcohols and polyethers such as decanol, glycerol, ethylene glycol, diethylene glycol, polyethylene glycol and / or copolymers with propylene glycol and / or fatty acids.

The invention also relates to a lubricating coating having an initial lubrication as measured on a Harland FTS Friction Test Apparatus of 20 g or less.

The hydrophilic coating according to the invention may be coated onto an article. The hydrophilic coating may be coated onto a substrate that may be selected from a range of geometries and materials. The substrate may have a texture such as porous, non-porous, smooth, regular or uneven roughness. The substrate supports the hydrophilic coating on its surface. The hydrophilic coating may be on all areas of the substrate or on selected areas. The hydrophilic coating may be applied to a variety of physical forms, including films, sheets, rods, tubes, molded parts (regular or irregular shape), fibers, fabrics and particulates. Suitable surfaces for use in the invention are surfaces that provide the desired properties, such as porosity, hydrophobicity, hydrophilicity, coloring ability, strength, flexibility, permeability, elongation abrasion resistance and tear resistance. Examples of suitable surfaces are, for example, surfaces consisting of or comprising metals, plastics, ceramics, glass and / or composites. The hydrophilic coating may be applied directly to said surfaces or may be applied to a pretreated or coated surface where the pretreatment or coating is designed to assist in adhering the hydrophilic coating to the substrate. In one embodiment of the invention the hydrophilic coating according to the invention is coated on a biomedical substrate. A biomedical substrate refers in part to the fields of medicine and the study of living cells and systems. These fields include diagnostic, therapeutic and experimental human medicine, veterinary medicine and agriculture. Examples of medical fields include ophthalmology, orthopedic and prosthetic, immunology, dermatology, pharmacology and surgery; Non-limiting examples of research fields include cell biology, microbiology, and chemistry. The term "biomedical" also refers to chemicals and chemical compositions, regardless of their source, that (i) mediate the biological response in vivo, (ii) are active in an in vitro assay or other model, for example, an immunological or pharmacological assay, or (iii) may be found within a cell or organism. The term "biomedical" also refers to separation sciences, such as those involving chromatography, osmosis, reverse osmosis, and filtration processes. Examples of biomedical articles include research tools, industrial and consumer applications. Biomedical articles include separation articles, implantable articles and ophthalmic articles. Ophthalmic items include soft and rigid contact lenses, intraocular lenses and forceps, retractors, or other surgical tools that contact the eyes or surrounding tissue. A preferred biomedical article is a soft contact lens made of silicon-containing hydrogel polymer, which is highly oxygen permeable. Separation articles include filters, osmosis and reverse osmosis membranes and dialysis membranes, as well as biosurfaces, such as faux fur or other membranes. Implantable articles include catheters and segments of artificial bone, joints or cartilage. An article may fall into more than one category, for example, an artificial skin is a porous, biomedical article. Examples of cell culture articles are glass beakers, plastic petri dishes and other implements employed in tissue cell culture or cell culture process. A preferred example of a cell culture article is a bioreactor micro carrier, a silicone polymer matrix employed in immobilized cell bioreactors, where the geometry, porosity, and density of the particulate carrier can be controlled to optimize performance. Ideally, the micro-vehicle is resistant to chemical or biological degradation, high impact stress, mechanical stress (agitation) and repeated steam or chemical sterilization. In addition to silicone polymers, other materials may also be suitable. This invention may also be applied in the food industry, the paper printing industry, hospital supplies, diapers and other coatings and other areas where hydrophilic, wetting or liquid transport articles are desired.

The medical device may be an implantable device or an extracorporeal device. The devices may be short term temporary use or a long term permanent implant. In certain embodiments, appropriate devices are those that are typically used to provide medical and / or diagnostic therapy in heart rhythm disorders, heart failure, valve disease, vascular disease, diabetes, neurological, orthopedic, neurosurgery, oncology and disease. , ophthalmology and surgery ENT.

Suitable examples of medical devices include but are not limited to stent, stent graft, anastomotic connector, synthetic patch, probe, electrode, needle, guidewire, catheter, sensor, surgical instrument, angioplasty balloon, wound drainage, shunts, tubing, infusion glove, urethral insertion, microsphere, implant, blood oxygenator, pump, vascular graft, vascular access port, heart valve, annuloplasty ring, suture, surgical forceps, surgical clamp, pacemaker, implantable defibrillator, neurostimulator, device orthopedic, cerebrospinal fluid shunt, implantable drug pump, spinal cage, artificial disc, pulp nucleus replacement device, atrial tube, intraocular lenses, and any tubing employed in minimally invasive surgery.

Articles that are specifically suitable for use in the present invention include medical devices or components such as catheters, for example, intermittent catheters, guidewires, stents, syringes, metal and plastic implants, contact lenses and medical tubing.

The hydrophilic coating formulation may be applied to the substrate, for example by dipping. Other application methods include spraying, washing, steaming, brushing, rolling and other methods known in the art.

The concentration of ionic or ionizable groups in the hydrophilic coating and the thickness of the hydrophilic coating according to the invention can be controlled by changing the type of polyelectrolyte, the hydrolytic coating formulation in the polyelectrolyte, the soaking time, the drag rate, the viscosity of the hydrophilic coating. hydrophilic coating formulation and the number of coating steps. Typically, the thickness of a hydrophilic coating on a substrate ranges from 0.1-300 μm, preferably 0.5-100 μm, more preferably 1-30 μm.

The invention further relates to a method for forming on a substrate a hydrophilic coating having a low coefficient of friction when moistened with a water-based liquid, wherein the hydrophilic coating comprises a polyelectrolyte,

To apply the hydrophilic coating to the substrate, a primer coating may be used to provide a bond between the hydrophilic coating and the substrate. Primer coating is often referred to as a primer coat, base coat or tail coat. Such primer coating is a coating that facilitates the adhesion of the hydrophilic coating to a given substrate as described, for example, in W002 / 10059. Bonding between the primer coating and the hydrophilic coating may occur due to covalent or ionic bonds, hydrogen bonding, physiosorption or polymer entanglement. Such primer coatings may be solvent-based, water-based (latex or emulsion) or solvent-free and may comprise linear, branched and / or crosslinked components. Typical primer coatings that may be used include, for example, polyether sulfones, polyurethanes, polyesters, including polyacrylates, as described, for example, in US 6,287,285, polyamides, polyethers, polyolefins and copolymers of the mentioned polymers.

Specifically, the primer coating comprises a support network, the support network optionally comprising a functional hydrophilic polymer entangled in the polymeric support network as described in W006 / 056482 A1. Information regarding the formulation of the initiator coating is incorporated herein by reference.

An initiator layer. As described above, it is specifically useful for improving the adhesion of a coating comprising a hydrophilic polymer, such as polylactam, specifically PVP and / or other hydrophilic polymers identified above, specifically to polyvinyl chloride (PVC), silicone, polyamide. polyester, polyolefin, such as polyethylene, polypropylene and ethylene propylene rubber (e.g. EPDM) or a surface having the same or less hydrophilicity.

In one embodiment, the surface of the article is subjected to oxidative, photo-oxidative and / or polarizing surface treatment, for example plasma and / or corona treatment, in order to improve the adhesion of the coating to be provided. Appropriate conditions are known in the art. Application of the formulation of the invention may be carried out in any case. Curing conditions may be determined based on known curing conditions for the photoinitiator and polymer or may be determined routinely.

Generally, curing may be performed at any appropriate temperature, depending on the substrate, as long as the medical or other properties of the article are not adversely affected to an unacceptable degree.

The intensity and wavelength of electromagnetic radiation can be routinely chosen at the photoinitiator of choice. Specifically, an appropriate wavelength in the UV, visible or part IV spectrum may be employed.

The invention will be further illustrated by the following examples.

Examples

In the following examples, hydrophilic coating formulations according to the invention and comparative coating formulations were applied to PVC pipes as described below and subsequently cured to form hydrophilic coatings according to the invention. PVC Male Catheters

Uncoated PVC pipes were coated with a hydrophilic coating. The PVC pipe had a length of 23 cm, an outside diameter of 4.5 mm (14 Fr) and an inside diameter of 3 mm. The pipes were sealed on one side to prevent the coating formulation from reaching the inside of the pipe during immersion.

Synthesis of PTGL 1000 (T-H) 2

In a dry, inert atmosphere toluene diisocyanate (TDI or T, Aldrich, 95% pure, 87.1 g, 0.5 mol), Irganox 1035 (Ciba Specialty Chemicals, 0.58 g, 1 wt.%). relative to ethyl hydroxy acrylate (HEA or H)) and tin (II) 2-ethyl hexanoate (Sigma, 95% pure, 0.2 g, 0.5 mol) were placed in a 1 liter flask and shaken for 30 minutes. The reaction mixture was cooled to 0 ° C using an ice bath. HEA (Aldrich, 96% pure, 58.1 g, 0.5 mol) was added dropwise within 30 minutes after which the ice bath was removed and the mixture was allowed to warm to room temperature. . After 3 hours, the reaction was complete. Poly (2-methyl-1,4-butanediol) -alt-poly (tetramethylene glycol) (PTGL, Hodogaya, Mn = 1,000 g / mol, 250 g, 0.25 mol) was added dropwise within 30 minutes. . Subsequently, the reaction mixture was heated to 60 ° C and stirred for 18 hours when the reaction was heated to 600 ° C and stirred for 18 hours when the reaction was complete as indicated by GPC (showing a complete consumption of HEA), IR (revealed no NCO-related ranges) and NCO titration (NCO content less than 0.02 wt%).

<table> table see original document page 29 </column> </row> <table> ZI

PTGL 1000 (T-H) 2 4.50% (w / w)

Polyvinylpyrolidone (1.3 Μ, Aldrich) 0.50% (w / w) (PVP)

Irgacure 2959 (Aldrich) 0.20% (w / w)

Ethanol (Merck pa) 94.8% (w / w)

Example 1. Hydrophilic Coating Formulation 5% (w / w) Polyethylene Glycol Diacrylate (PEG4000DA)

Polyethylene oxide with Mn = 200,000 3.75% (w / w) g / mol (PEO 200K) (Aldrich)

Sodium salt Partial poly (acrylamide-co 1.25% (wt / wt) acrylic acid) (14.5 wt.% Na +), 20 wt.% Acrylamide (PAcA) (Aldrich)

Irgacure 2959 0.1% (w / w)

Tween 80 (surfactant) (Merck) 0.01% (w / w)

Distilled water 44.94% (weight / weight)

Methanol (Merck pa) 44.95% (w / w)

Example 2. Hydrophilic Coating Formulation PEG4 000DA 5% (w / w)

PEO 200K 3.75% (weight / weight)

PAcA 1.25% (weight / weight)

Irgacure 2959 0.1% (w / w)

Distilled water 44.95% (weight / weight)

Methanol 44.95% (weight / weight)

Example 3. PVP Hydrophilic Coating Formulation 5% (w / w)

PAcA 1.25% (weight / weight)

Benzophenone 0.1% (w / w) <table> table see original document page 31 </column> </row> <table> Example 6. Hydrophilic Coating Formulation

<table> table see original document page 32 </column> </row> <table> Distilled water Methanol

46.67 wt% 46.67 wt%

All ingredients were obtained commercially.

It has been found that the coating obtained after curing the formulation of Example 7 is lubricant, having good drying time and sufficient adherence to the PVC catheter also after gamma sterilization. No visible cracks were observed with the naked eye. Synthesis of PEG4000DA

150 g (75 mmol 0H) of polyethylene glycol (PEG,

Fluka Biochemika Ultra, OH value 28.02 mg KOH / g,

4 99.5 mew / kg, Mn = 4004 g / mol) was dissolved in 350 mL

of dry toluene at 450 ° C under nitrogen atmosphere. 0.2 g

(0.15% by weight) of Irganox 1035 was added as a

radical stabilizer. The resulting solution was

azeotropically distilled throughout. The. night (50 ° C, 70 mbar) conducting the condensed toluene to 4Άmol cells. For each PEG batch the OH value was accurately determined by OH titration, which was performed according to the method described in the 4th edition of the European Pharmacopoeia, paragraph 2.5.3, Hydroxyl Value, page 105. This made it possible to calculate the amount of acryloyl chloride to be added and determination of the degree of esterification of acrylate during the reaction. 9.1 g (90 mmol) of triethylamine was added to the reaction mixture, followed by a dropwise addition of 8.15 g (90 mmol) of acryloyl chloride dissolved in 50 mL of toluene in 1 hour. Triethylamine and acryloyl chloride were colorless liquids. The reaction mixture was stirred for 2 hours at 4 hours at 45 ° C under nitrogen atmosphere. During the reaction, the temperature was maintained at 45 ° C to prevent PEG crystallization. In order to determine conversion, a sample was taken from the reaction mixture, dried and dissolved in deuterated chloroform. Trifluoroacetic anhydride (TFAA) was added and a 1 H-NMR spectrum was recorded. TFAA reacts with any remaining hydroxyl groups to form a trifluoro acetic ester, which can be easily selected using IH-NMR spectroscopy (the triple signal of the methylene protons at the α position of the trifluoro acetic acid group (g, 4.45 ppm) can be clearly distinguished from the signal of the methylene groups at the α position of the acrylate ester (d, 4.3 ppm)). When the degree of esterification was 98%, an additional 10 mmol of acryloyl chloride and triethylamine was added to the reaction mixture, allowing it to react for 1 hour. At an acrylate esterification degree> 98%, the heated solution was filtered to remove triethylamine hydrochloride salts. Approximately 300 mL of toluene was removed under vacuum (50 ° C, 20 mbar). The remaining solution was kept at 45 ° C in a heated dropping funnel and added dropwise to 1 liter of diethyl ether (cooled in an ice bath). The ether suspension was cooled for 1 hour before the PEG diacrylate product was obtained by filtration. The product was dried overnight at room temperature under reduced air atmosphere (300 mbar). Yield: 80-90% as white crystals. Coating and curing process for Examples 1-7 and

Comparative Experiments A-D

The PCV piping was first dipped with the primer coating formulation and cured using a Harland PCX / 175/24 coater according to the dipping protocol for the primer coating in Table 2. Subsequently, the hydrophilic coating formulation was applied and cured using a Harland PCX / 175/24 Coater according to the dipping protocol for the hydrophilic coating. The Harland PCX / 175/24 Coater has been equipped with a Harland Medical Systems UVM 400 lamp. The lamp intensity of the Harland PCX / 175/24 Coater averaged 60 mW / cm2 and was measured using a Solatell Sola Sensor 1 equipped with an International Ligth Detector SED005 number 989, Optical Input: W number 11521, Filter: wbs320 number 27794. The International Light IL14 00A instruction manual has been applied which is available on the Internet: www.intl-light.com. The UV dose was approximately 1.8 J / cm2 for the primer coating and 21.6 J / cm2 for the hydrophilic coating = Qiaanto for the coating parameters applied see Table 1.

Visual inspection of the coated PVC pipes showed good wetting of the hydrophilic coating. A uniform coating was obtained.

Table 1. Applied coating parameters

<table> table see original document page 35 </column> </row> <table> <table> table see original document page 36 </column> </row> <table> <table> table see original document page 37 < / column> </row> <table>

Test Methods

Lubrication Test

Lubrication tests were performed on a Harland FTS5000 Friction Test Device (HFT). The protocol has been selected: see table 2 for HFT settings. Harland Medical Friction Test Device Pads, P / N 102692, FTS5000 Friction Test Device Pads with 0.125 * 0.5 ** 0.125 Durometer Durometer were employed.

Subsequently, the desired test description was entered when "test operation" was activated. After inserting a guide swivel into the catheter, it was attached to the clip. The device was adjusted downstream to the desired direction such that the catheter was soaked with demineralized water for 1 minute. After zero calibration in water the protocol was activated by pressing "start". Data was saved after termination. The clip was removed from the force gauge and subsequently the catheter was removed from the clip.

Table 2. HFT Settings

<table> table see original document page 37 </column> </row> <table> <table> table see original document page 38 </column> </row> <table>

Drying Time

Duration is defined here as the duration of the coating as a lubricant after the device has been removed from the wetting fluid where it has been stored and / or moistened. Drying time can be determined by measuring friction in grams as a function of the time the catheter was exposed to air in HFT (see above). Drying time is the point in time where the friction reaches a value of 20 g or greater, or in a more rigid test of 15 g or more as measured at a temperature of 22 ° C and a relative humidity of 35%. After insertion of the guidewire into the coated PCV male catheter, the catheter was attached to the clip. The catheter was soaked with demineralized water for 1 minute. The clamp with the catheter was placed at the force gauge and the device was sent downstream to the desired position and the test was started immediately according to the same lubrication test settings. Measurements were observed after 1, 2, 5, 7.5, 10, 12.5 and 15 minutes. The pads of the friction tester were cleaned and dried after measurement. Data was saved after termination. The clip was removed from the force gauge and subsequently the catheter was removed from the clip.

Table 3 provides lubrication as a function of time of the lubricant coating prepared in accordance with Examples 1-5, as well as the results of Comparative Experiments A and B. Table 3. Lubrication as a function of time of the lubricant coating. librification prepared according to Examples 1-5 and Comparative Experiments AB.

<table> table see original document page 39 </column> </row> <table>

The table shows that lubrication is significantly higher (i.e. friction is lower) for the lubricant coatings according to the invention (Examples 1-5) comprising partial poly (acrylamide-co-acrylic acid) sodium salt, poly (acrylic acid) sodium salt or poly (acrylic acid-co-maleic acid) sodium salt, relative to the lubricating coatings of Comparative Experiments AeB which do not comprise a polyelectrolyte. The lubricant coating according to the invention remained lubricant for a longer period in the drying test than in the comparative example coatings. Table 4 provides the lubrication of the lubricant coatings prepared according to Example 6 and the CeD Comparative Experiments.

Table 4. Lubrication of the lubricant coating prepared according to Example 6 and Comparative Experiments C-D.

<table> table see original document page 40 </column> </row> <table>

The table shows that coatings according to Example 6 are more lubricating (i.e. lower friction values) than coatings according to Comparative Experiment C, which involves a coating formulation comprising a hydrophilic, nonionic, but non-ionic polymer. without polyelectrolyte or Example D, which involves a coating formulation comprising a polyelectrolyte, but without hydrophilic, nonionic polymer. Lubrication measurement results as a function of time (Table 3) and lubrication measurements show that the combination of a polyelectrolyte and a nonionic hydrophilic polymer results in increased lubrication and longer coating drying time.

Claims (20)

1. Hydrophilic coating formulation which, when cured, results in a hydrophilic coating, characterized in that the hydrophilic coating formulation comprises a polyelectrolyte and a nonionic hydrophilic polymer. Hydrophilic coating formulation according to claim 1, characterized in that the polyelectrolyte is chosen from the group consisting of homo salts and acrylic acid copolymers, homo salts and methacrylic acid copolymers, maleic acid homo and copolymers, homo salts and fumaric acid copolymers, homo salts and monomer copolymers comprising sulfonic acid groups, homo and monomer copolymers comprising quaternary ammonium salts and mixtures and / or derivatives thereof. Hydrophilic coating formulation according to either claim 1 or claim 2, characterized in that the polyelectrolyte is a copolymeric polyelectrolyte, where the copolymeric polyelectrolyte is a copolymer comprising at least two different types of constitutional units, where at least one type of constitutional units comprises ionizable or ionized groups and at least one type of constitutional units is not found in ionizable or ionized groups. Hydrophilic coating formulation according to any one of claims 1, 2 or 3, characterized in that the polyelectrolyte is selected from the group consisting of poly (acrylamide-co-acrylic acid) salts, poly (methacrylamide) salts. co-acrylic acid), poly (acrylamide-co-methacrylic acid) salts, poly (methacrylamide-co-methacrylic acid) salts, poly (acrylamide-co-maleic acid) salts, poly (methacrylamide-co-acid acid) salts -maleic), poly (acrylamide co-dialkyl ammonium chloride), or poly (co-diallyldimethyl ammonium chloride). Hydrophilic coating formulation according to any one of claims 1, 2, 3 or 4, characterized in that the non-ionic hydrophilic polymer is selected from the group consisting of poly (lactams), for example polyvinylpyrrolidone (PVP). ), polyurethanes, homo and copolymers of acrylic and methacrylic acid, polyvinyl acid, polyvinyl ethers, maleic anhydride-based copolymers, polyesters, vinylamines, polyethyleneimines, poly (carboxylic acids), polyamides, polyanhydrides, polyphosphenes, polyphosphenes for example methyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose and hydroxypropylcellulose, heparin, dextran, polypeptides e.g. collagen, fibrin and elastin, polysaccharides e.g. chitosan, hyaluronic acid, alginates, gelatin and chitin, polyesters e.g. polylactides, polyglycolides and polycaprolactones, polypeptides, for example collagen, albumin, oligo peptides, polypeptides, short chain peptides, proteins and oligonucleotides. Hydrophilic coating formulation according to any one of claims 1, 2, 3, 4 or 5, characterized in that the hydrophilic coating formulation further comprises a support monomer and / or polymer comprising several reactive fractions capable of undergoing crosslinking reactions. Hydrophilic coating formulation according to claim 6, characterized in that the support monomer and / or polymer is a hydrophilic support monomer and / or polymer. Hydrophilic coating formulation according to any one of claims 1, 2, 3, 4, 5, 6 or 7, characterized in that the hydrophilic coating formulation further comprises at least one surfactant. Hydrophilic coating formulation according to any one of Claims 1, 2, 3, 4, 5, 6, 7 or 8, characterized in that the hydrophilic coating formulation further comprises at least one plasticizer =. Hydrophilic coating, characterized in that it is obtained by curing the hydrophilic coating formulation of any one of claims 1, 2, 3, 4, 5, - 6, 7, 8 or 9. Lubricating coating, characterized in that it is obtained by applying wetting fluid to a hydrophilic coating of claim 10. 12. Lubricating coating, characterized in that it has an initial lubrication of 20 g or less after 1 cycle as measured on a Harland FTS friction tester. Lubricating coating according to claim 11, characterized in that it has an initial lubrication of 20 g or less after 1 cycle as measured on a Harland FTS friction tester. Coating system for preparing a lubricant coating, said coating system comprising a coating formulation comprising a hydrophilic, nonionic polymer and a wetting fluid having a polyelectrolyte. Coating system for preparing a lubricant coating, said coating system comprising a coating formulation of any one of claims 1, 2, 3, 4, -5, 6, 7, 8 or 9. and a wetting fluid comprising a polyelectrolyte. 16. Use of a polyelectrolyte and a nonionic hydrophilic polymer characterized in that it is in a lubricant coating in order to improve the drying time of the lubricant coating, where the drying time is defined as the duration of time the coating remains lubricated after a device comprising the lubricant coating has been removed from the wetting fluid, where it has been stored and / or wetted, which is determined by measuring friction in grams as a function of time on the Harland FTS friction tester. Article, characterized in that it comprises at least one hydrophilic coating or lubricating coating of any one of claims 10, 11, 12 or 13. An article according to claim 17, characterized in that the article is a medical device or component. Medical device or component according to claim 18, characterized in that it comprises a catheter, a medical tubing, a guidewire, a bookcase or a membrane. A method for forming a hydrophilic coating on a substrate, the method comprising: applying a hydrophilic coating formulation of any one of claims 1, 2, 3, 4, 5, -6, 7, 8. or 9 to at least one surface of the article; - and allowing the coating formulation to cure by exposing it to electromagnetic radiation, thereby activating the initiator.